A functional single-nucleotide polymorphism in the CR1 promoter region contributes to protection against cerebral malaria.
BACKGROUND
Although the level of erythrocyte complement receptor type 1 (E-CR1) expression in patients with malaria has been extensively studied, whether the level of expression of E-CR1 is associated with severe malaria remains controversial. The present study examined a possible association of polymorphisms in the CR1 gene with the severity of malaria, and it evaluated the influence of the associated polymorphism on expression of E-CR1.


METHODS
Seventeen single-nucleotide polymorphisms in CR1 were genotyped in 477 Thai patients who had Plasmodium falciparum malaria (203 had mild malaria, 165 had noncerebral severe malaria, and 109 had cerebral malaria). The E-CR1 expression level was measured by flow cytometry in 24 healthy Thai subjects.


RESULTS
The T allele of the reference single-nucleotide polymorphism rs9429942 in the CR1 promoter region was strongly associated with protection against cerebral malaria (2.2% of patients with mild malaria vs. 7.8% of patients with cerebral malaria; P = .0009; Bonferroni-adjusted Pc = .0306. The E-CR1 expression level was significantly higher in individuals with the TT genotype of rs9429942 than in individuals with the TC genotype of rs9429942 (P = .0282).


CONCLUSIONS
We identified a CR1 promoter allele, associated with higher E-CR1 expression, that conferred protection against cerebral malaria. Previous studies have shown that the rate of clearance of immune complexes (ICs) from the circulation is related to the E-CR1 level. These results lead to the hypothesis that the clearance of ICs regulated by E-CR1 therefore plays a crucial role in the pathogenesis of cerebral malaria.
Teeranaipong
Phairote
P
Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Ohashi
Jun
J
Patarapotikul
Jintana
J
Kimura
Ryosuke
R
Nuchnoi
Pornlada
P
Hananantachai
Hathairad
H
Naka
Izumi
I
Putaporntip
Chaturong
C
Jongwutiwes
Somchai
S
Tokunaga
Katsushi
K
D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D016779:Malaria, Cerebral / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017463:Receptors, Complement 3b / Q000235:genetics*
C509991:CR1 protein, human; D017463:Receptors, Complement 3b